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Science. 2015 Aug 7;349(6248):606-13. doi: 10.1126/science.aaa4282. Epub 2015 Jul 9.

IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.

Author information

  • 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
  • 2St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. jmarkle@rockefeller.edu jean-laurent.casanova@rockefeller.edu.
  • 3Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
  • 4Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
  • 5Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
  • 6Department of Immunology, School of Medicine, Universidad de Valparaíso, Santiago, Chile. Department of Pediatrics, Padre Hurtado Hospital and Clinica Alemana, Santiago, Chile.
  • 7Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 8Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 9Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 10Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 11Institut Curie, INSERM U932, Paris, France.
  • 12Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 13Caritas Baby Hospital, Post Office Box 11535, Jerusalem, Israel.
  • 14Department of Immunology, School of Medicine, Universidad de Valparaíso, Santiago, Chile.
  • 15St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
  • 16Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France.
  • 17Trudeau Institute, Saranac Lake, NY 12983, USA.
  • 18La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
  • 19Department of Radiology, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.
  • 20Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
  • 21Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
  • 22Laboratoire Dynamique du Génome et Système Immunitaire, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
  • 23Laboratoire Dynamique du Génome et Système Immunitaire, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
  • 24Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne NE4 6BE, UK.
  • 25Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
  • 26Department of Paediatric Allergy Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
  • 27St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
  • 28Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
  • 29St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France.
  • 30Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA. Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA.
  • 31Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. Center of Medical Immunology, Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
  • 32St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
  • 33St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. Howard Hughes Medical Institute, New York, NY 10065, USA. jmarkle@rockefeller.edu jean-laurent.casanova@rockefeller.edu.

Abstract

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

Copyright © 2015, American Association for the Advancement of Science.

PMID:
26160376
[PubMed - indexed for MEDLINE]
PMCID:
PMC4668938
Free PMC Article

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